Hyperandrogenism of adrenal origin. Treatment and symptoms of hyperandrogenism in women Hyperandrogenism syndrome of complex origin

I found this very detailed article. a lot of words, but I hope it helps someone

R.A.MANUSHAROVA, MD, Professor, E.I.CHERKIZOVA, sci.m.s., Department of Endocrinology and Diabetology with a Course of Endocrine Surgery, GOU DPO RMA PO, Moscow

"Hyperandrogenism", or " hyperandrogenemia", - this term refers to an increased level of male sex hormones () in the blood of women. Hyperandrogenism syndrome implies the appearance in women under the action of androgens of signs characteristic of men: hair growth on the face and body according to the male pattern; the appearance of acne on the skin; hair loss on head (alopecia); decreased voice timbre (baryphonia); change in physique (masculinization - masculinus - "male" phenotype) with the expansion of the shoulder girdle and narrowing of the hips. The most frequent and earliest manifestation of hyperandrogenism is hirsutism - excessive hair growth in androgen-dependent women zones, male pattern hair growth.Hair growth with hirsutism is noted on the abdomen in the midline, face, chest, inner thighs, lower back, in the intergluteal fold.

Women with hyperandrogenism are at increased risk for complications of childbirth. The most frequent of them are untimely rupture of amniotic fluid and weakness of labor activity.

It is necessary to distinguish between hirsutism and hypertrichosis - excessive hair growth in any part of the body, including those where hair growth does not depend on androgens.
Hypertrichosis can be either congenital (inherited in an autosomal dominant manner) or acquired as a result of anorexia nervosa, porphyria, and also occur with the use of certain drugs: phenotoin, cyclosporine, diazoxide, anabolic steroids, etc.

There are three stages of hair growth: the growth stage (anagen), the transitional stage (catagen), and the resting stage (telogen). During the last stage, the hair falls out.

Androgens affect hair growth depending on their type and location. Yes, on early stages sexual development under the influence of a small amount of androgens, hair growth begins in the axillary and pubic areas. With more androgens, hair appears on the chest, abdomen and face, and with a very high level, hair growth on the head is suppressed and bald patches appear above the forehead. Moreover, androgens do not affect the growth of vellus hair, eyelashes and eyebrows.

The severity of hirsutism is often arbitrarily defined and graded as mild, moderate, or severe. One of the objective methods for assessing the severity of hirsutism is the Ferrimann and Gallway scale (1961). On this scale, androgen-dependent hair growth is assessed in 9 areas of the body in points from 0 to 4. If the total score is more than 8, hirsutism is diagnosed.

With functional hyperandrogenism (polycystic ovary syndrome (PCOS), ovarian thecamatosis, etc.), hirsutism develops gradually, accompanied by the appearance of acne, weight gain and irregular menstruation. The sudden appearance of hirsutism with signs of rapidly developing virilization may indicate androgen-producing tumors of the ovaries or adrenal glands.

Hyperandrogenism- an increase in the level of male sex hormones in the blood of women, leads to a violation menstrual cycle, excessive hair growth, virilization, infertility.

In hyperandrogenism, tissue sensitivity to insulin is often impaired. The level of insulin in the blood in this condition rises and the risk of developing diabetes increases.

An increase in the amount of male sex hormones may be associated with the pathology of other endocrine organs, for example thyroid gland or the pituitary gland. With neuroendocrine syndrome (impaired function of the hypothalamus and pituitary gland), the disease is accompanied by a significant increase in body weight.

The main androgens include testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) and its sulfate, androstenedione, d5 - androstenediol, d4 - androstenedione.

Testosterone is synthesized from cholesterol, which enters the human body with animal products or synthesized in the liver, and is delivered to the outer mitochondrial membrane. Transport of cholesterol to the inner membrane of mitochondria is a gonadotropin-dependent process. On the inner membrane of mitochondria, cholesterol is converted to pregnenalone (the reaction is carried out by cytochrome P450). In the smooth endoplasmic reticulum, following two pathways for the synthesis of sex hormones: d5 (mainly in the adrenal glands) and d4 (mainly in the ovaries), subsequent reactions are carried out. Biologically available is free and albumin-bound testosterone.

In women, testosterone is produced in the ovaries and adrenal glands. In the blood, 2% of testosterone circulates in a free state, 54% is associated with albumin, and 44% is with globulin-binding sex steroids. The level of SHBG is increased by estrogens, and lowered by androgens, therefore, in men, the level of SHBG is 2 times lower than in women.

A decrease in the level of SHBG in the blood plasma is observed with:

• obesity
• excessive formation of androgens;
• treatment with corticosteroids;
• hypothyroidism;
• acromegaly.

An increase in the level of SHPS occurs when:

• estrogen treatment;
• pregnancy;
• hyperthyroidism;
• cirrhosis of the liver.

Testosterone associated with SHPS performs some of the functions on the cell membrane, but cannot penetrate inside. Free testosterone can, by converting to 5a-DHT or by binding to a receptor, penetrate into target cells. Biologically available is the sum of the fractions of free and albumin-bound testosterone.

The testicles, ovaries, and adrenal glands produce dehydroepiandrosterone (DHEA). It was first isolated in 1931 and is a weak androgen. After being converted to testosterone in peripheral tissues, it has an effect on the cardiovascular and immune systems.
Androstenedione, a precursor of testosterone, is produced in the testicles, ovaries, and adrenal glands. The conversion of androstenedione to testosterone is a reversible process.

Androgens carry out their action at the cellular level through high-affinity nuclear receptors. Under the action of the aromatase enzyme, androgens are converted into estrogens.
Free testosterone enters the target cell and binds to the androgen receptor on the DNA of the X chromosome. Testosterone or DHT, depending on the activity of 5a-reductase in the target cell, interacts with the androgen receptor and changes its configuration, resulting in a change in the receptor dimers that are transmitted to the cell nucleus and interact with the target DNA.

Dehydrotestosterone, then testosterone, has a high affinity for androgen receptors, and adrenal androgens (DHEA, androstenedione) have a low affinity.
The effects of testosterone include: differentiation of male sexual characteristics; the appearance of secondary sexual characteristics; growth of male genital organs; pubic hair; hair growth in the armpits and on the face; growth spurt during puberty; closure of the epiphyses; the growth of the "Adam's apple"; thickening of the vocal cords; increase in muscle mass, thickening of the skin; functioning of the sebaceous glands. Testosterone also affects libido and potency, increases aggression.

With hyperandrogenism, it is noted:

• hair growth on the face and body according to the male pattern;
• the appearance of acne on the skin;
• hair loss on the head (alopecia);
• lowering the timbre of the voice (baryphony);
• change in physique (masculinization) with the expansion of the shoulder girdle and narrowing of the hips.

Hyperandrogenism develops with the following diseases of the hypothalamic-pituitary system:

• neuroendocrine-exchange syndrome with obesity and gonadotropic
  dysfunction;
• corticotropinoma (Itsenko-Cushing's disease);
• somatotropinoma (acromegaly);
• functional hyperprolactimemia and on the background of prolactinoma;
• gonadotropinoma, hormonally inactive pituitary adenoma, "empty" sella syndrome;
• anorexia nervosa;
• obesity and type 2 diabetes;
• insulin resistance syndromes (including acanthosis nigricans type A (insulin receptor gene mutation) and leprechaunism);
• secondary hypothyroidism.

There are ovarian and adrenal forms of hyperandrogenism, each of which has tumor and non-tumor forms. Non-tumor or functional hyperandrogenism of ovarian genesis indicates PCOS, stromal hyperplasia and ovarian thecamatosis, and functional hyperandrogenism of adrenal genesis testifies to congenital adrenal cortex dysfunction (VDC). The tumor form of hyperandrogenism causes androgen-producing tumors of the ovaries or adrenal glands. With corticosteroma, pronounced hyperandrogenism is observed.

Treatment of a non-classical form of congenital adrenal dysfunction should begin with the suppression of elevated levels of ACTH (corticotropin). For this purpose, dexamethasone is used. In equivalent doses, it has a more pronounced effect compared to other glucocorticoids and retains fluid to a lesser extent. When treating with dexamethasone, it is necessary to control the concentration of cortisol. Control is carried out in the morning.

In patients with VDKN, after taking adequate doses of dexamethasone, the menstrual cycle, as a rule, is restored, and in the majority it becomes ovulatory.

In the absence of ovulation while taking glucocorticoid drugs with a non-classical form of VDKN or with insufficiency of the luteal phase of the menstrual cycle, clomiphene citrate (clostilbegit (Egis, Hungary); Clomid (Hoechst Marion RousseI, Germany) is prescribed according to the generally accepted scheme from 5 to 9 or from 3 to 7 days of the menstrual cycle.Due to the similarity with estrogen receptors in target cells in the ovaries, pituitary gland and hypothalamus, the drug clomiphene citrate has two opposite effects: a weak estrogenic and a pronounced antiestrogenic.Due to the fact that the effectiveness of therapy is noted in the suppression of androgen synthesis adrenal glands, stimulation of ovulation should be carried out while taking glucocorticoids.

In women on the background of combined therapy, ovulation often occurs and pregnancy occurs. Termination of glucocorticoid treatment after pregnancy may lead to spontaneous miscarriage or cessation of development of a fertilized egg, so therapy should be continued.

Gonadotropic drugs LH and FSH can be used to stimulate ovulation according to the usual scheme, but always while taking glucocorticoids.

If against the background of therapy with clostilbegit on the days of the alleged ovulation (13-14 days of the cycle) the insufficiency of the corpus luteum phase persists, then preparations containing gonadotropins (LH and FSH) are administered: profazi, pregnil, pergonal, etc. in large doses (5000-10,000 ED). It should be remembered that the use of these drugs may develop ovarian hyperstimulation syndrome (OHSS).

Surgical treatment is indicated for patients with VDKN over the age of 30 years with ineffective treatment of infertility for more than 3 years and the presence of an ultrasound picture of polycystic ovaries - laparoscopic wedge resection, demedulation or electrocauterization of the ovaries. At the same time, treatment with glucocorticoids is continued.
Low- and microdose combined oral contraceptives (COCs) with antiandrogenic activity are used to treat patients with VDKN and severe hirsutism. The most effective among them are: Diane-35, Zhanin, Yarina, etc. These drugs contain estrogens and gestagens. Under the influence of estrogens, the production of sex steroid-binding globulin (SHBG) in the liver is enhanced, which is accompanied by an increase in androgen binding. As a result, the content of free androgens decreases, which reduces the manifestations of hirsutism. The antigonadotropic effect of these drugs suppresses the formation of gonadotropins in the anterior pituitary gland, and the gonadotropic function of the pituitary gland in VDKN is inhibited by a high level of androgens circulating in the blood. Therefore, the action of COCs can lead to an even greater decrease in the concentration of gonadotropins and aggravate menstrual irregularities. In this regard, the use of COCs in VDKN should not be long-term.

Treatment of androgen-producing ovarian tumors. In order to detect metastases, an examination of the pelvis and omentum is performed. Chemotherapy is performed when distant metastases are detected. In the absence of signs of malignant growth and dissemination in such patients of reproductive age, unilateral adnexectomy is performed, and in postmenopausal women, extirpation of the uterus with appendages is performed. After the operation, dynamic monitoring of patients, control of hormone levels, ultrasound of the pelvic organs is necessary. In the absence of metastases and dissemination after removal of the ovarian tumor in patients of reproductive age, complete recovery occurs: the symptoms of virilization disappear, the menstrual cycle and fertility are restored. Ten-year survival depends on the histological features and size of the tumor and is 60-90%.

In hormonally active tumors of the adrenal glands, surgery is indicated, since there is no conservative treatment. A contraindication is only a pronounced dissemination of the process. With decompensation of the cardiovascular system, purulent complications postpone the operation. In this case, according to indications, cardiac, hypotensive, sedatives are prescribed; patients with diabetes before surgery, they are transferred to therapy with simple insulin in fractional doses.

Surgical access depends on the size and location of the tumor. Recently, surgical treatment on the adrenal glands is carried out by the laparoscopic method. The course of the postoperative period depends on the degree and type of hormonal activity of the tumor and the metabolic disorders caused by it. Therefore, patients need to prescribe specific hormonal therapy.

Treatment of idiopathic hirsutism. For the treatment of idiopathic hirsutism, antiandrogens are used - modern microdosed drugs containing estrogens and gestagens in their composition. Diane-35 in combination with androcur, as well as Zhanin, Belara, Yarina, has the highest antiandrogenic activity among these drugs.

In addition to combined oral contraceptives, androgen antagonists are prescribed:

• spironolactone, which inhibits 5a-reductase at the cellular level and reduces the rate of conversion of testosterone to dihydrotestosterone;
• cyproterone acetate - a progestin that blocks androgen receptors at the cellular level;
• cimetidine - antagonist histamine receptors blocking the action of androgens at the cellular level;
• desogestrel, ketoconazole, metrodin - increasing the level of SHBG, binding testosterone and making it biologically inactive;
• flutamide, a non-steroidal antiandrogen that binds to androgen receptors, inhibits testosterone synthesis to a lesser extent;
• finasteride - which has an antiandrogenic effect due to inhibition of 5a-reductase activity and does not affect androgen receptors;
• ketocanazole - inhibitory steroidogenesis;
• medroxyprogesterone - suppressing the secretion of gonadoliberin and gonadotropins, reducing the secretion of testosterone and estrogens;
• analogues of gonadotropin-releasing hormone (GnRH) - acting on the functional state of the ovaries, suppressing the secretion of estrogens, androgens;
• glucocorticoids.

In the absence of the effect of the use of combined oral contraceptives, the appointment of flutamide reduces hair growth, reduces the level of androstenedione, dihydrotestosterone, LH and FSH. COCs and flutamide can cause the following side effects: dry skin, hot flashes, increased appetite, headache, dizziness, breast engorgement, decreased sex drive, etc.

The use of ketoconazole is accompanied by a significant decrease in the level of androstenedione, total and free testosterone in the blood serum. A decrease in androgen levels leads to a weakening or elimination of hair growth.

Medroxyprogesterone acts on the level of globulin that binds sex hormones, reducing the content of the latter. When using the drug, 95% of patients note a decrease in hirsutism. When using the drug, the following may occur side effects: amenorrhea, headache, edema, weight gain, depression, changes in biochemical parameters of liver function.

The use of GnRH analogues causes reversible medical castration, which is accompanied by a decrease in hirsutism. However, their use for more than 6 months leads to the development of postmenopausal symptoms (hot flashes, feeling hot, vaginal dryness, dyspareunia, osteoporosis). The development of the above symptoms prevents the appointment of estrogens or COCs simultaneously with GnRH analogues.

With an increased level of dehydroepiandrosterone or 17 OH-progesterone in the blood, glucocorticoids are prescribed. Of these, dexamethasone is the most effective. Against the background of taking the drug in patients, hirsutism decreases and other symptoms of hyperandrogenism disappear. When prescribing dexamethasone to patients, it is possible to suppress the pituitary-adrenal system, so it is necessary to control the level of cortisol in the blood.

Treatment of polycystic ovary syndrome

In the treatment of PCOS, it is necessary to restore the ovulatory menstrual cycle and fertility, eliminate the manifestations of androgen-dependent dermopathy; normalize body weight and correct metabolic disorders; prevent late complications of PCOS.
Insulin resistance (IR) and its potentiating obesity is the most important pathogenetic link of anovulation in PCOS.

In the presence of obesity (BMI>25 kg/m2), PCOS treatment should begin with weight loss. Weight loss drugs are prescribed against the background of a low-calorie diet containing no more than 25-30% fat, 55-60% slowly digestible carbohydrates, 15% protein from the total calorie intake. Salt intake is limited. Diet therapy must be combined with increased physical activity.

Excess body weight in PCOS causes hyperinsulinemia (HI) and decreased sensitivity of peripheral tissues to insulin (IR). However, a number of studies have shown that with PCOS, insulin sensitivity is reduced in patients not only with increased, but also with normal or reduced BMI. Thus, PCOS is an independent factor that reduces tissue susceptibility to insulin. Obesity, observed in 50-70% of patients with PCOS, has an independent negative effect, potentiating IR.

To remove IR, biguanides are prescribed. Metformin (Siofor, Verlin Chemie, Germany) is used in Russia. The use of this drug in PCOS reduces blood glucose levels, inhibits gluconeogenesis in the liver and increases the sensitivity of peripheral tissues to insulin. As a result of the use of metformin, body weight decreases, the menstrual cycle normalizes, the level of testosterone in the blood decreases, but ovulation and pregnancy are not always observed.

Ovulation induction is the second step in the treatment of PCOS. But with a combination of obesity and PCOS, ovulation stimulation is considered a medical error. After normalization of body weight, clomiphene is prescribed to stimulate ovulation. If stimulation is ineffective after 6 months of treatment, the patient can be considered clomiphene resistant. It is observed in 20-30% of patients with PCOS. In this case, FSH preparations are prescribed: menogon - human menopausal gonadotropin or synthesized recombinant FSH. GnRH analogues are prescribed for patients with PCOS and high LH levels. Under the influence of these drugs, desensitization of the pituitary gland occurs, which increases the frequency of ovulation after the administration of FSH preparations.

If the effect of conservative therapy absent, resort to surgical stimulation of ovulation. Laparoscopic access is performed wedge resection or demedulation or cautery of both ovaries. The use of the endoscopic method of intervention made it possible to significantly reduce the incidence of adhesions in comparison with laparotomy.

Surgical treatment of PCOS is used in the following cases:

• with a combination of PCOS with recurrent dysfunctional uterine bleeding and endometrial hyperplasia, regardless of the presence or absence of obesity;
• in women with normal body weight with a significant increase in the level of LH in the blood plasma;
• in women over 35 years of age, even in the presence of obesity. In this case, intensive therapy of obesity is carried out immediately after the operation.

The following factors can lead to a decrease in the frequency of regulation of the menstrual cycle and the onset of pregnancy:

• the duration of anovulation and the age of a woman over 30;
• ovaries big size with a subcapsular arrangement of atretic follicles around a hyperplastic stroma;
• pronounced IR and GI regardless of body weight;
• violation of the menstrual cycle by the type of amenorrhea.

Treatment of hirsutism in PCOS. For the treatment of hirsutism in PCOS, the same drugs are used as for the treatment of idiopathic hirsutism (see above).

Due to the fact that hirsutism is caused by hyperandrogenism, drugs that reduce the level of androgens that suppress androgen receptors are used for treatment; reducing the formation of androgens; inhibitory enzyme systems involved in the synthesis of androgens, in the production of (extragonadal) testosterone and its conversion to DHT.

Due to the fact that the treatment of hirsutism with medical methods is a long process, many women use different kinds hair removal (electric, laser, chemical, mechanical, photoepilation).

Treatment of complications of PCOS

To prevent the development of metabolic disorders, it is necessary to reduce body weight. To prevent the development of endometrial hyperplasia, it is necessary to conduct ultrasound monitoring of the state of the endometrium and, if necessary, treat with progesterone derivatives. In the presence of GE (endometrial thickness more than 12 mm), curettage of the uterine mucosa is prescribed under the control of hysteroscopy, and a histological examination is also carried out.
In addition to restoring fertility, treatment of PCOS should be carried out in order to correct metabolic disorders that are the background for the onset of type 2 diabetes mellitus, early atherosclerosis, hypertension, as well as high risk development of hyperplasia and adenocarcinoma of the endometrium.

In medicine, such a problem as hyperandrogenism in women is known. Causes, symptoms, treatment for such a diagnosis require the assessment and participation of qualified doctors. And although this disease is extremely difficult to overcome completely, it is better to contact the doctors without delay.

The essence of the disease

When it comes to a disease such as hyperandrogenism in women, the causes of symptoms, treatment and preventive measures are always associated with such a problem as the effect of androgens on the body. This process leads to the appearance of female appearance masculine traits and other not very pleasant changes. In more detail, we are talking about such manifestations as the appearance of vegetation on the face and body, a low voice, as well as changes in some elements of the figure.

It is worth noting the fact that this pathology of the female endocrine system is common, and can not only lead to unpleasant external changes, but also cause infertility. Therefore, when the first symptoms of hyperandrogenism appear, you should immediately plan a visit to the doctor.

Why does pathology develop

The topic "hyperandrogenism in women: causes, symptoms, treatment" is very important for the fairer sex, since this problem occurs in approximately 20% of patients. Therefore, it makes sense to pay attention to those factors and processes that lead to the development of this disease.

As the main cause, AGS can be identified - adrenogenital syndrome. The bottom line is that the adrenal glands are capable of producing many other hormones besides androgens, such as glucocorticoids. The latter appear under the influence of a certain enzyme. The basis for their occurrence are the accumulated androgens. Sometimes women already have an enzyme defect at birth, as a result of which male hormones are not converted, but accumulate on an ongoing basis, causing unpleasant changes in female body.

There is another process due to which hyperandrogenism of adrenal origin develops. We are talking about tumors of the adrenal glands. They are also formed against the background of an increase in the concentration of androgens.

The risk of developing the pathology mentioned above also appears in the case when the production of male hormones in the ovaries of a woman occurs. Moreover, cells that produce androgens can cause tumors to form in the ovarian region.

Hyperandrogenism syndrome is sometimes the result of exposure to pathologies of other endocrine organs, such as the pituitary gland.

Signs of androgen excess

If we talk about the clinical symptoms of an increased concentration of the male hormone, then they can be described as follows:

• acne;
• hair loss and bald patches in the forehead (androgenetic alopecia);

• the sebaceous glands begin to produce an excessive amount of secretion, as a result of which the fat content of the skin increases;
• baryphony, which means lowering the timbre of the voice;
• hair appears on the abdomen and chest.

It is worth noting the fact that hirsutism - excessive growth of terminal hair on the female body, is diagnosed in 80% of patients with such a problem as hyperandrogenism syndrome.

With a similar disease, some representatives of the weaker sex may have a violation of the menstrual cycle, a complete absence of menstruation, as well as obesity, infertility and hypertension.

The concentration of male hormones can cause an increase in the susceptibility of the female body to infections of various types. Fatigue and a tendency to depression are also possible.

Acne and sebaceous glands

To clearly understand what to do with such a problem as hyperandrogenism in women, the causes, symptoms, treatment and diagnosis should be considered thoroughly. Since the factors that cause the development of the disease were discussed above, it makes sense to study the features of the symptoms.

If we touch on such a problem as acne, it is worth noting that they are the result of keratinization of the walls of the follicle and increased production of sebum, which is stimulated by the concentration of androgens, including in plasma. With such symptoms, as a rule, COCs or antiandrogens are prescribed, which can significantly improve the patient's condition.

Also, under the influence of male hormones in androgen-dependent zones, pigmented, thick, coarse hair appears instead of vellus. This usually happens during puberty. At the same time, the effect of androgen on the region of the eyebrows, eyelashes, temporal and occipital parts remains minimal.

Adrenal hyperandrogenism

It is worth recalling that the adrenal glands are two endocrine glands that are located directly above the kidneys themselves.

They are the source of 95% of the produced androgen (DEA-sulfate). The complexity of hyperandrogenism associated with these glands comes down to the fact that the pathology is congenital and makes itself felt against the background of androgenital syndrome. It leads to a critical decrease in the level of enzymes in the female body that are necessary for the production of hormones such as glucocorticoids.

Hyperandrogenism of adrenal genesis is caused precisely by this deficiency, which leads to an increase in the concentration of other hormones - pregnenolone, progesterone, etc. Such changes result in increased production of androgen in the female body.

Sometimes a pathology is diagnosed that was caused by tumors of the adrenal glands that secrete the male hormone. According to statistics, such a form of the disease as adrenal hyperandrogenism is recorded in 30-50% of women who have problems with androgen.

Impact on the ovaries

A high concentration of male hormones can also affect the functioning of the ovaries. In most cases, this problem makes itself felt through two forms: hyperthecosis and polycystic. It is important to pay attention to the fact that the risk of developing this pathology in women increases with regular strength sports.

Ovarian hyperandrogenism is a consequence of slowing down the growth of follicles under the influence of androgens. Since the ovaries consist of them, the result of such processes is the overgrowth of the latter. The medical name for this problem is follicular atresia.

But these are not all the difficulties that accompany ovarian hyperandrogenism of genesis. The bottom line is that the male hormone plays the role of a factor against which the pathological formation of fibrous tissue develops. connective tissue leading to polycystic. In this situation, the good news is the fact that only 5% of women face such a problem.

It is also worth noting that given form hyperandrogenism in the fairer sex is the cause of failure of the central regulation of androgen levels. This process occurs at the level of the hypothalamus and pituitary gland. As a result, the hormonal background changes significantly.

Signs to look out for

There are a number of symptoms that indicate the appearance of the problem described above. The fact that there is such a pathology as ovarian hyperandrogenism of genesis can be found in the following manifestations:

• osteoporosis;
• seborrhea;
• on the face, in addition to acne, peeling and inflammation appear, which are difficult to neutralize with the usual cosmetic methods;
• amyotrophy;
• excess weight;
• change in the proportions of the female body - masculinization;
• coarsening of the voice (baryphony);
• hair growth all over the body, even on the face;
• the formation of bald patches on the head.

In addition, there are many more secondary symptoms such as increased blood glucose levels, arterial hypertension, decreased immunity, etc.

Excess weight

Obesity in women can be caused by the ovarian hyperandrogenism described above. With this form of pathology, an increase in the level of estradiol is often recorded.

Doctors conducted a study, according to which the following information was confirmed: both the high level of the male hormone and the estrogens that form under its influence have the most direct effect on the development of obesity corresponding to the male type.

Such processes are the cause of an increase in insulin dependence and a subsequent increase in the concentration of the male hormone in the body of women suffering from the pathology described above. In some cases, androgens do not affect a woman's weight through the central nervous system.

mixed form

Doctors with a certain frequency have to deal with the manifestation of several forms of hyperandrogenism. This situation is explained by the fact that at the same time there is a violation of the ovaries.

The possibility of such a complication is important to consider when studying the dangers of hyperandrogenism in women. In essence, this is what happens: adrenal androgens, concentrating in the adrenal glands, thereby increase the level of the male hormone in the ovaries. This process also occurs in the blood, which leads to increased production of luteinizing hormone. The latter, in turn, provokes the appearance of hyperandrogenic syndrome.

The occurrence of a mixed form of pathology may be due to severe injuries, intoxication of the brain or

Diagnostics

Initially, the doctor must separate hyperandrogenism from other diseases against which it develops (acromegaly, liver disease, etc.). The next step is to determine the hormonal level. This procedure should be carried out on an empty stomach in the morning. A similar analysis must be performed three times, since at a high concentration of androgen it constantly changes.

Attention is drawn to the level of dehydroepiandrosterone, the high content of which will indicate adrenal hyperandrogenism. The level of ketosteroids in the urine is also important. If its content goes beyond the norm, then it makes sense to suspect the development of pathology.

Treatment Methods

Hyperandrogenism is too serious a problem to ignore the help of qualified doctors. And if we analyze the entire course of treatment, we can conclude that it is aimed at achieving 4 key goals:

• elimination of manifestations on the skin;
• normalization of the menstrual cycle;
• treatment of infertility that was caused by anovulation;
• elimination and prevention of metabolic disorders associated with the underlying disease.

A diet for hyperandrogenism in women is prescribed in case of a significant increase in weight. In this case, it is important to strictly adhere to all the recommendations of the doctor, only if this condition is observed, you can get the desired result.

Those patients who intend to have a child, in most cases, are prescribed hormone therapy that can ensure full ovulation.

Women who do not plan to become pregnant are treated with oral contraceptives and, in some cases, wedge ovarian excision.

Drugs for the treatment of hyperandrogenism in women are also actively used if the body is not able to neutralize the high level of androgen on its own. We are talking about such drugs as "Metipred", "Dexamethasone", etc. Surgical intervention can be prescribed if the pathology is provoked by a tumor.

Results

The high concentration of the male hormone in the female body is more than a serious problem that often develops against the background of no less dangerous diseases. Therefore, when the first symptoms appear, diagnosis and treatment must be carried out without fail.

Hyperandrogenism is an endocrine disease caused by increased secretion of male sex hormones in a woman's body. Androgens are produced by the ovaries and adrenal cortex. Depending on the primary cause of the pathology, may differ clinical symptoms.

Hyperandrogenism in women causes increased secretion of luteinizing hormone in the pituitary gland, which blocks the release of follicle-stimulating hormone and estradiol. As a result, the process of maturation of the follicle is disrupted, the release of the egg (anovulation) does not occur. High levels of androgens contribute to the formation of multiple cysts in the ovaries (polycystic ovary syndrome).

Male hormones reduce the susceptibility of peripheral tissues to insulin, which leads to an increase in blood glucose levels, impaired glucose tolerance, carbohydrate metabolism and the development of type 2 diabetes mellitus.

Classify true and idiopathic hyperandrogenism. In the first case, the level of androgens in the woman's blood is increased, and in the second, the sensitivity of peripheral tissue receptors to male hormones is increased.

Causes of pathology

What is hyperandrogenism and why does it occur? The main causes of the disease are:

• tumors, adrenal metastases;
• violation of the hypothalamic-pituitary regulation caused by injuries, tumors, inflammatory diseases brain;
• ovarian tumors: luteoma, thecoma;
• androgenital syndrome is a congenital pathology of the adrenal cortex, in which increased production testosterone.

In women, the causes of hyperandrogenism cause a violation of the hormonal balance, the functioning of the reproductive system, and metabolic processes in the body.

Symptoms of ovarian hyperandrogenism

The disease is of ovarian and adrenal origin - depending on the organ, which begins to intensively produce androgens. Ovarian hyperandrogenism in most cases develops against the background of polycystic ovary syndrome, less often pathology is caused by hormone-producing tumors.

PCOS is characterized by irregular menstruation, infertility, and increased levels of androgens in the blood. The figure of the girl changes according to the male type, hair on the face and body begins to grow, the volume of the waist and chest increases, the fat layer is deposited in the lower abdomen. The work of the sebaceous glands is disrupted, seborrhea appears, an acne rash that cannot be treated. Stretch marks appear on the skin of the thighs and buttocks. Sleep apnea (breath holding) leads to insomnia.

Pictured is a woman with characteristic features hirsutism.

The characteristic symptoms of hyperandrogenism in PCOS are the appearance of premenstrual syndrome. Women become irritable, their mood often changes, they are worried about migraine, intense pain in the lower abdomen, swelling, soreness of the mammary glands.

The ovaries increase in size by 2-3 times, their capsule thickens. Inside the organ are found multiple cystic formations. Hormonal imbalance causes thickening and hyperplasia of the endometrium of the uterus, menstruation becomes longer, more abundant, with the release of blood clots.

Symptoms of adrenal hyperandrogenism

This type of virilization develops against the background of androgenital syndrome. This is hereditary disease, which causes increased secretion of androgens in the adrenal cortex. The congenital deficiency of organ enzymes is compensated by the body up to a certain point, but when exposed to a number of factors, hormonal balance is disturbed. Pregnancy, severe stress, the onset of sexual activity can provoke such a condition.

The cause of adrenal hyperandrogenism can be hormone-producing tumors, Itsenko-Cushing's disease, hyperprolactinemia, acromegaly. Cancer cells in the reticular zone of the cortical layer produce "weak" androgens. In the process of metabolism, male hormones turn into a more active form and change the overall hormonal background of a woman. Obesity contributes to the acceleration of these processes.

Adrenal hyperandrogenism causes cyclic disturbances in the ovaries due to an increase in estrogen levels, suppression of the growth and maturation of the follicle occurs, the menstrual cycle is disturbed, and menstruation may completely stop. The process of ovulation does not occur, a woman cannot become pregnant and bear a child.

Symptoms of adrenal hyperandrogenism in girls:

• deformation of the external genital organs at birth, it is difficult to determine the sex of a child (female hermaphroditism);
• delayed sexual development, menarche begins at the age of 15–16, the menstrual cycle is irregular, accompanied by profuse blood loss;
• in girls in adolescence, signs of hirsutism are observed: hair grows on the face and body like in men;
• acne, seborrhea, skin pigmentation;
• partial atrophy of the mammary glands;
• an increase in the size of the clitoris;
• alopecia - hair loss on the head;
• the figure changes: narrow hips, broad shoulders, short stature;
• rough voice.

In women of reproductive age, adrenal hyperandrogenism leads to early abortion. This is caused by the cessation of growth of the uterus due to the formation of an inferior corpus luteum. In most girls, menstrual and reproductive function is completely disrupted, infertility develops, and sexual desire increases. Hirsutism is weakly expressed, physique does not change, metabolic processes are not disturbed.

Mixed type of hyperandrogenism

Hyperandrogenism of mixed origin is manifested by symptoms of the ovarian and adrenal forms of the disease. In women, polycystic ovaries and signs of androgenital syndrome are found.

Manifestations of a mixed type of disease:

• acne
• striae;
• elevated blood pressure;
• violation of the menstrual cycle, amenorrhea;
• cysts in the ovaries;
• infertility, early termination of pregnancy;
• impaired glucose tolerance or high blood sugar;
• elevated levels of low density lipoproteins.

Hyperandrogenism can be caused by systemic diseases that affect the adrenal cortex, ovaries or brain, and disrupt metabolism. These are pituitary adenomas, anorexia nervosa, schizophrenia, type 2 diabetes mellitus, acromegaly, prolactinoma.

Peripheral and central hyperandrogenism

With damage to the central nervous system, inflammatory, infectious diseases or intoxication of the body, the secretion of gonadotropic hormones of the pituitary gland, which are responsible for the production of luteinizing and follicle-stimulating hormone, can be suppressed. As a result, the process of maturation of the follicle in the ovary and the synthesis of sex hormones are disrupted, androgen production increases.

Women show symptoms of polycystic disease, ovarian dysfunction, menstrual disorders, skin rashes, PMS.

Peripheral hyperandrogenism is caused by an increase in the activity of a skin enzyme, sebaceous gland 5-α-reductase, which converts testosterone to the more potent androgen dihydrotestosterone. This leads to hirsutism of varying severity, the appearance of acne vulgaris.

Hyperandrogenism during pregnancy

In pregnant women, an increase in androgen levels is the cause of spontaneous abortion. The most dangerous terms are the first 7–8 and 28–30 weeks. In 40% of patients, intrauterine fetal hypoxia is observed, most often this occurs in the third trimester. Another complication is late toxicosis, while kidney function worsens, blood pressure rises, and body edema appears.

Hyperandrogenism during pregnancy can lead to premature discharge of amniotic fluid, complicated childbirth. Changes in the hormonal background negatively affect the development of the child, infants may be disturbed cerebral circulation, there are signs of intrauterine malnutrition.

Hyperandrogenism and pregnancy are reasons for urgent hormone therapy to prevent abortion and other complications. Women who have previously had miscarriages, miscarriage, increased levels of male hormones should be carefully examined at the stage of pregnancy planning.

Diagnosis of the disease

Diagnosis - hyperandrogenism is established according to the results of laboratory tests on the level of hormones. With polycystic ovary syndrome in the blood of a woman, the level of testosterone, androstenedione, luteinizing hormone increases. The concentration of FSH, prolactin, DHEA in the blood and 17-KS in the urine remains within the normal range. The ratio of LH/FSH is increased by 3-4 times. With hormone-dependent ovarian tumors, the level of testosterone and prolactin in the blood is significantly increased.

The mixed form of the disease is characterized by a slight increase in the level of testosterone, LH, DHEA-S in the blood and 17-KS in the urine. The concentration of prolactin is normal, and estradiol and FSH are reduced. The ratio of LH / FSH is 3.2.

To determine the primary cause of hyperandrogenism, tests are carried out with Dexamethasone and chorionic gonadotropin. A positive hCG test confirms polycystic ovarian disease, which causes a hormonal imbalance. A negative response indicates the adrenal nature of hyperandrogenism.

The Abraham test allows you to identify a disease of adrenal origin, with the introduction of synthetic glucocorticoids, the synthesis of ACTH in the anterior pituitary gland is suppressed, which stops the stimulation of the adrenal cortex. If the result is positive, it is adrenal hyperandrogenism, a negative response may be a sign of a cortical tumor.

Additionally, ultrasound of the ovaries is performed to detect cysts, changes in the size and structure of the organ. Electroencephalography, MRI, CT of the brain are indicated for suspected damage to the pituitary gland.

Treatment Methods

Therapy is prescribed individually for each patient. Androgen receptor blockers reduce the effect of male hormones on the skin, ovaries (Flutamide, Spironolactone). Androgen secretion inhibitors inhibit the production of testosterone by the endocrine glands (cyproterone acetate). These funds restore the balance of hormones, eliminate the symptoms of pathology.

Hyperandrogenism of the adrenal glands is compensated by glucocorticoids, which suppress the excess of androgens. Women are prescribed Dexamethasone, Prednisolone, they are also taken during pregnancy if the expectant mother has an increased level of testosterone. It is especially important to be treated in a timely manner for girls who have close relatives with congenital androgenital syndrome. The dosage and duration of the medication is prescribed by the doctor.

Hormonal treatment of hyperandrogenism is carried out with glucocorticosteroids, combined oral contraceptives (Diana-35), GnRH agonists. Such drugs are treated with mild hyperandrogenism of ovarian origin, PCOS.

Non-drug treatment

To restore hormonal balance, women are advised to regularly engage in moderate physical activity, give up bad habits, and lead a healthy lifestyle. It is important to adhere to the diet, to make a balanced diet that excludes coffee, alcohol, carbohydrates, animal fats. It is useful to eat fresh fruits, vegetables, dairy products, dietary meats and fish. Pharmaceutical preparations are taken to compensate for the deficiency of vitamins.

Treatment folk remedies can only be carried out in combination with the main therapy. You should first consult a doctor.

Hyperandrogenism causes disturbances in the work of many organs and systems, leads to the development of adrenal and ovarian insufficiency, infertility, and type 2 diabetes mellitus. To prevent the appearance of symptoms of hirsutism, skin rashes, metabolic syndrome, hormone therapy is indicated.

Bibliography

1. Kozlova V.I., Pukhner A.F. Viral, chlamydial and mycoplasmal diseases of the genitals. Guide for doctors. St. Petersburg 2000.-574 p.
2. Miscarriage, infection, innate immunity; Makarov O.V., Bakhareva I.V. (Gankovskaya L.V., Gankovskaya O.A., Kovalchuk L.V.) - "GEOTAR - Media". - Moscow. - 73 p.-2007.
3. Emergency conditions in obstetrics and gynecology: diagnosis and treatment. Pearlman M., Tintinalli J. 2008 Publisher: Binom. Knowledge Lab.
4. Adamyan L.V. etc. Malformations of the uterus and vagina. – M.: Medicine, 1998.

Content

Ovarian hyperandrogenism is a common endocrine pathology. This condition is diagnosed by gynecologists in 4-5% of patients. It occurs if in the female body, male sex hormones begin to be produced in excess by the ovaries.

Varieties and causes of the syndrome

Gynecologists distinguish hyperandrogenism of adrenal, ovarian and mixed genesis. Pathology can be hereditary or acquired. It is primary and secondary.

Most often, ovarian hyperandrogenism occurs with such diseases:

• primary polycystic ovaries, which is formed in adolescent girls;
• polycystic ovary syndrome (secondary polycystic);
• hyperthecosis, causes hyperandrogenic symptoms in postmenopausal women.

Hyperandrogenism occurs when an excessive amount of androgens is produced in the body or their increased formation from the precursors of androgenic hormones is observed. The specified diagnosis is also established if, against the background of a normal concentration of androgens, the susceptibility of target tissues to them increases.

Attention! In rare cases, pathology occurs due to the fact that in the body of a woman the level of globulins, which are needed to bind sex hormones, is lowered.

Globulins are necessary to prevent the interaction of androgens and specific receptors. Signs of androgenism may appear with ovarian tumors. There are certain forms oncological diseases in which androgen hypersecretion is observed.

Symptoms of hyperandrogenism in women

Hyperandrogenism in patients is accompanied by an extensive list of gynecological, cosmetic and dysmetabolic signs. You can suspect the development of pathology by the following symptoms:

• violation of the regularity of the menstrual cycle;
• amenorrhea;
• anovulatory menstrual cycles;
• damage to the skin, most often women complain of acne, dry skin with flaky areas, seborrhea, alopecia;
• hirustism (increased male pattern hair growth);
• the appearance of excess weight;
• impaired glucose tolerance;
• amyotrophy;
• coarsening of the voice.

With congenital hyperandrogenism, anomalies in the development of the genital organs are observed. During a gynecological examination, the doctor may reveal clitoral hypertrophy, partial fusion of the urogenital sinus, and labia majora.

Most often, pathology is detected when women turn to a gynecologist about infertility. Some have mild hyperandrogenism of ovarian origin. In this case, there may be no external changes, and the level of androgens in the blood is within the normal range. To clarify the diagnosis, the patient is assigned a comprehensive medical examination.

Diagnostics

To establish a diagnosis, a gynecologist:

• collects anamnesis;
• conducts examination and two-hand examination;
• prescribes ultrasound diagnostics;
• gives directions for blood and urine tests.

The patient needs to determine the concentration of steroid hormones in the body. It is recommended to pass tests to determine the level:

• testosterone (total, free);
• DHEA-S;
• GSPS.

With hyperandrogenism of ovarian genesis, an increase in ASD and testosterone is observed. An excessively high level of total testosterone or DHEA-S may indicate the development of a tumor that synthesizes androgens.

With polycystic ovary syndrome, you need to not only look at the content of male hormones, but also check the overall hormonal background. Pathology is accompanied by:

• balancing the content of testosterone and luteinizing hormone;
• a decrease in the content of follicle-stimulating hormone;
• an increase in the concentration of prolactin.

With the disease, an increase in blood glucose is observed. The diagnosis can only be established by an experienced gynecologist, taking into account the examination data, instrumental examination, information from the collected patient history and test results.

Treatment Methods

The choice of therapy tactics should be carried out by the attending gynecologist, taking into account the underlying disease, which led to the development of hyperandrogenic syndrome.

With polycystic ovaries, hormonal therapy is selected. Patients with hirustisoma may be prescribed Medroxyprogesterone, Spironolactone. If necessary, patients are selected oral contraceptives that have an antiandrogenic effect. Often gynecologists prescribe Diana-35. Under influence hormonal pills the process of ovulation, the production of gonadotropins is inhibited, the production of ovarian hormones is suppressed. As a result, androgen receptors are blocked, testosterone and SHPS do not rise.

Patients who developed hyperandrogenism during the postmenopausal period are prescribed Klimen. If androgen-secreting malignant tumors of the ovaries are detected, the treatment should be selected by a gynecologist-oncologist. Most patients are prescribed surgical treatment, chemopreventive and radiation therapy. With the appearance of benign neoplasms that produce androgens, surgical removal is indicated.

Attention! Overweight women are prescribed diet and exercise. Weight loss contributes to the normalization of hormonal levels.

Forecast

Many women, with the right treatment tactics, manage to stop hyperandrogenism of ovarian origin. With polycystic ovaries, good results are observed with conservative therapy. Properly selected treatment allows you to restore ovulation, normalize the regularity of the menstrual cycle. If conservative therapy is ineffective, electrocoagulation of the ovaries is prescribed.

In the treatment of hyperandrogenism, not only the work of the reproductive organs is normalized, but also cosmetic defects are reduced. They can also be eliminated with the help of cosmetic manipulations. But they will be effective provided that the woman is undergoing treatment aimed at getting rid of the underlying pathology.

Ovarian hyperandrogenism occurs in patients with hormonal disorders that have arisen against the background of polycystic ovaries, tumors or hyperthecosis. Treatment should be selected by a gynecologist after a full examination of the patient and clarification of the cause that provoked the appearance of hyperandrogenic symptoms. You can find out how androgenism manifests itself, what tests are needed to establish a diagnosis, how treatment is carried out, you can from the video

For citation: Pischulin A.A., Karpova E.A. Ovarian hyperandrogenism and metabolic syndrome // BC. 2001. No. 2. S. 93

Endocrinological science Center RAMS, Moscow

With the syndrome of ovarian hyperandrogenism of non-tumor origin or hyperandrogenic ovarian dysfunction, previously called Stein-Leventhal syndrome, is currently, according to the WHO classification, better known in the world literature as polycystic ovary syndrome (SPY).

The clinical picture of PCOS is manifested by a chronic anovulatory state of the ovaries or severe hypofunction of the corpus luteum, which leads to a bilateral increase in the size of the ovaries with thickening and sclerosis of the albuginea. These changes are manifested by a violation of the menstrual function - opsomenorrhea, amenorrhea, but the development of metrorrhagia is not excluded. Violations of folliculogenesis lead to the development of anovulatory primary or secondary infertility.

One of the main diagnostic criteria for PCOS is hyperandrogenemia. - an increase in the level of androgenic steroids in the blood (such as testosterone, androstenedione), which leads to the development of hirsutism and other androgen-dependent dermopathies.

Obesity or overweight often accompanies PCOS. Determination of body mass index (BMI) allows you to identify the degree of obesity. Measurement of indicators of waist (WT) and hips (HB) and their ratio indicates the type of obesity (abdominal type of obesity is unfavorable prognostically, in which WT/HB > 0.85).

In addition to the main symptoms of the disease, the clinical picture is largely determined by general metabolic disorders, such as dyslipidemia, impaired carbohydrate metabolism, and an increased risk of developing hyperplastic and tumor processes in the genitals. Dyslipidemia is an increase in triglycerides, cholesterol, low density lipoprotein, very low density lipoprotein and a decrease in high density lipoprotein. These disorders lead to the risk of early development of atherosclerotic vascular changes, hypertension and coronary heart disease.

Carbohydrate metabolism disorders consist in the development of the insulin resistance-hyperinsulinemia complex, which has recently been the main direction in the study of the pathogenetic links in the development of PCOS.

In the 60s, the pathogenesis of PCOS was associated with a primary enzymatic defect in ovarian 19-hydroxylase and/or 3b-dehydrogenase, combining these disorders under the concept of primary polycystic ovaries. However, in the works of subsequent years, it was shown that the aromatase activity of granulosa cells is an FSH-dependent function.

An increased level of luteinizing hormone (LH), the absence of its ovulatory peak, a normal or reduced level of follicle-stimulating hormone (FSH) with an impaired LH/FSH ratio (2.5-3) detected in PCOS suggested a primary violation of gonadotropic regulation of steroidogenesis in the ovarian tissue with the development of a secondary polycystic ovaries.

Until the mid-1980s, it was believed (the theory of S.S.C. Yen) that the trigger mechanism in the pathogenesis of PCOS is the excessive synthesis of androgens by the adrenal glands during the adrenarche period as a result of an altered sensitivity of the adrenal glands to ACTH or excessive stimulation of the reticular zone of the adrenal cortex by a non-ACTH-like factor or under the influence of b -endorphins, neurotransmitters, such as dopamine. When a critical body weight is reached (especially when its norm is exceeded), the peripheral conversion of androgens to estrogens increases, primarily in the liver and adipose tissue. An increase in the level of estrogens, primarily estrone, leads to hypersensitization of gonadotrophs in relation to luliberin (GnRH). At the same time, under the action of estrone, the production of GnRH by the hypothalamus increases, the amplitude and frequency of impulses of its secretion increase, as a result of which the production of LH by the adenohypophysis increases, the LH / FSH ratio is disturbed, and relative FSH deficiency occurs. Strengthening the effect of LH on the ovaries contributes to an increase in the production of androgens by the thecal cells and their hyperplasia. A relatively low level of FSH leads to a decrease in the activity of FSH-dependent aromatase, and granulosa cells lose their ability to aromatize androgens into estrogens. Hyperandrogenism prevents the normal growth of follicles and contributes to the formation of their cystic atresia. Lack of growth and maturation of follicles further inhibits FSH secretion. The increased pool of androgens in peripheral tissues is converted into estrone. A vicious circle is closing.

Thus, the result of a violation of the central and peripheral mechanisms of regulation of steroidogenesis is the development of functional ovarian hyperandrogenism in patients with PCOS.

The pathogenesis of PCOS according to S.S.C. Yen is shown in Diagram 1:

Scheme 1.

In the early 80s, a number of authors proposed a new theory of the pathogenesis of polycystic ovary syndrome, different from the theory of S.S.C. Yen. It has been found that PCOS is associated with hyperinsulinemia, and this syndrome is characterized by both reproductive and metabolic disorders.

The relationship between hyperinsulinemia and hyperandrogenism was already pointed out in 1921 by Achard and Thieris. They described hyperandrogenism in an obese woman with type 2 diabetes and called the condition "bearded woman's diabetes."

Later, D. Bargen found that women with PCOS and hyperandrogenism had basal and glucose-stimulated hyperinsulinemia compared with the control group of women of the same weight, which suggested the presence of insulin resistance. A direct relationship between insulin and androgen levels was revealed, and it was suggested that hyperinsulinemia may be the cause of hyperandrogenism.

In 1988, G. Reaven first suggested that IR and compensatory hyperinsulinemia (GI) play a major role in the development of the syndrome of metabolic disorders. He called him "Syndrome X" . Currently, the term "metabolic syndrome" or "insulin resistance syndrome" is most often used.

Hypotheses of the pathogenesis of hyperinsulinemia and hyperandrogenism

The mechanism of occurrence of hyperandrogenism and hyperinsulinemia is not fully understood. Theoretically, three interactions are possible: hyperandrogenism (GA) causes GI; GI leads to GA: there is some third factor responsible for both phenomena.

1. The assumption that GA causes GI is based on the following facts. In women who take oral contraceptives containing progestins with "androgenic properties", impaired glucose tolerance is detected. Long-term administration of testosterone to transsexuals is accompanied by the occurrence of IR. It has been shown that androgens affect the composition of muscle tissue by increasing the number of muscle fibers of the second type, which are less sensitive to insulin compared to the fibers of the first type.

2. Most factors are in favor of GI leading to GA. It has been shown that IR persists in patients undergoing subtotal or total ovarian removal, as well as in women who have long-term use of GnRH agonists, when marked androgen suppression was noted. The administration of diazoxide, a drug that suppresses the release of insulin from the pancreas, caused a decrease in testosterone (T) levels and an increase in the level of sex steroid-binding globulin (SSBG) in patients with PCOS, obesity and hyperinsulinemia. Intravenous administration insulin in women with PCOS led to an increase in circulating levels of androstenedione and T. Measures aimed at increasing insulin sensitivity (weight loss, fasting and a low-calorie diet) were accompanied by a decrease in androgen levels. There is evidence that insulin can directly suppress the production of SHBG by the liver, and in conditions of hyperinsulinemia this effect is enhanced. At the same time, it is believed that insulin, and not sex hormones, is the main regulator of SSSH synthesis. A decrease in the level of SSSG leads to an increase in the concentration of free and, therefore, biologically active T (normally 98% of T is in a bound state).

The hypothesis linking GA with hyperinsulinemia does not answer the question of how the ovary maintains insulin sensitivity in an insulin-resistant state of the body. Several possible explanations have been proposed. Since insulin has many functions, it can be assumed that some of them are selectively defective. Organ-specific insulin sensitivity may be observed. But more likely is the assumption that insulin acts on the ovary not only through insulin receptors, but also through receptors for insulin-like growth factors (IGF).

Insulin receptors and IGF-1 receptors have been identified in human ovaries (ovarian stromal tissue of healthy women, women with PCOS, follicular tissue and granulosa cells). Insulin can bind to IGF-1 receptors, although with less affinity than its own receptors. However, in HI, as well as in situations where insulin receptors are blocked or deficient, it can be expected that insulin will bind to IGF-1 receptors to a greater extent.

It is possible that the mechanisms of insulin/IGF-1 stimulation of steroidogenesis in the ovary can be divided into non-specific and specific. Nonspecific are the classical action of insulin on the metabolism of glucose, amino acids and DNA synthesis. As a result, the viability of the cell increases and, consequently, the synthesis of hormones increases. Specific mechanisms include direct action of insulin/IGF-1 on steroidogenic enzymes, synergism between insulin and LH/FSH, and effects on the number of LH receptors.

Insulin / IGF-1, acting synergistically with FSH, stimulates aromatase activity in granulosa cell culture and thereby increases the synthesis of estradiol. In addition, they lead to an increase in the concentration of LH receptors, enhancing LH-dependent synthesis of androstenedione by theca- and stromal cells.

The increasing concentration of androgens in the ovary under the action of insulin/IGF-1 causes atresia of the follicles, which leads to the gradual elimination of estrogen- and progesterone-producing granulosa cells, followed by hyperplasia of the thecal cells and luteinization of the interstitial tissue of the ovary, which are the site of androgen production. This explains the fact that the stimulation of ovarian steroidogenesis by insulin manifests itself mainly in the form of hyperandrogenism.

It has been suggested that insulin/IGF-1 can stimulate both LH-dependent cytochrome P450c17a activity in the ovaries and ACTH-dependent P450c17a activity in the adrenal glands. This, apparently, explains the frequent combination of ovarian and adrenal forms of hyperandrogenism in patients with PCOS.

A relationship with the S.S.C. theory is also possible. Yen on the involvement of adrenal steroidogenesis in the pathogenesis of PCOS (Figure 2).

Scheme 2. The action of insulin in polycystic ovary syndrome

V. Insler (1993), having studied the levels of insulin, IGF-1, growth hormone and their correlation with the levels of gonadotropins and androgens in women with PCOS, proposed two models for the development of this syndrome. In obese patients, GI causes an excess production of androgens through IGF-1 receptors, which, acting in synergy with LH, cause an increase in the activity of cytochrome P450c17a, the main controlling enzyme in androgen synthesis. In patients with normal body weight, a relative increase in the concentration of growth hormone stimulates excessive production of IGF-1. From this point on, synergism with LH leads to androgen hyperproduction by the same mechanism as in obese patients. An increase in the level of androgens causes a change in the function of the hypothalamic centers, leading to a violation of the secretion of gonadotropins and changes typical for PCOS (Scheme 3).

Scheme 3. Pathogenesis of polycystic ovary syndrome

The molecular mechanisms leading to the development of insulin resistance are not fully understood. However, recent advances in molecular biology have made it possible to determine the structure of the gene encoding the insulin receptor in women with ovarian hyperandrogenism.

Moller and Flier studied the sequence of amino acids in the structure of DNA chains in patients with ovarian hyperandrogenism. They found a substitution of tryptophan for serosine at codon 1200. The researchers suggested that this change disrupts the activation of the tyrosine kinase system in the insulin receptor. Low activity of insulin receptors leads to the development of IR and compensatory GI.

Yoshimasa et al. described another point mutation variant in a patient with hyperandrogenism, insulin resistance, and acanthosis nigricans. They found a substitution of serine for arginine in the tetrameric structure of the insulin receptor. This mutation in the active locus resulted in the impossibility of connecting the a- and b-subunits, as a result of which the functionally active receptor was not synthesized. These studies are only the first attempts to identify a specific genetic etiology of ovarian stromal tecomatosis.

Later, Dunaif A. notes that in polycystic ovary syndrome, IR may be due to impaired autophosphorylation of the insulin receptor b-subunits (iR), the cytoplasmic part of which has tyrosine kinase activity. At the same time, insulin-independent phosphorylation of serine residues (CPOS-ser) increases with suppression of tyrosine kinase activity (a secondary signal transmitter that determines insulin sensitivity to the receptors of the same name). This defect is typical only for PCOS-dependent IR; in other insulin-resistant states (obesity, NIDDM), these changes are not detected.

It cannot be ruled out that some serine phosphorylating factor exists in PCOS-ser. For example, a serine/threonine phosphatase inhibitor is isolated, which, apparently, disrupts uR phosphorylation in PCOS-ser. This compound is similar to the recently isolated membrane glycoprotein PC-1 (inhibitor of insulin receptor tyrosine kinase), but the latter does not increase insulin-independent phosphorylation of serine and R.

Tumor necrosis factor-a (TNF-a) has similar properties: phosphorylation of serine residues IRS-1 (one of the secondary transmitters of the uR signal) under the influence of TNF-a leads to suppression of tyrosine kinase activity of uR.

Moller et al. found that phosphorylation of human P450c17 serine, a key enzyme regulating the biosynthesis of adrenal and ovarian androgens, increased 17,20-lyase activity. Modulation of the enzymatic activity of steroidogenesis by serine phosphorylation has been described for 17b-hydroxysteroid dehydrogenase. If we assume that the same factor (enzyme) phosphorylates insulin receptor serine, causing IR, and P450c17 serine, causing hyperandrogenism, then the relationship between PCOS and IR can be explained. In vitro experiments have shown that protein kinase A (serine/threonine kinase) catalyses serine phosphorylation of insulin receptors (Scheme 4).

Scheme 4. Insulin resistance gene in PCOS

Thus, according to the results of a study conducted by Brzechffa et al. (1996), a significant proportion of women in the PCOS population have leptin levels higher than expected based on their BMI, free testosterone, and insulin sensitivity. On the other hand, recent work in this area has not shown significant differences in leptin levels in the study groups with PCOS and in the control groups. In addition, it was found that the content of leptin is not affected by the basal level of insulin, the content of gonadotropins and sex steroids. However, Zachow and Magffin (1997), taking into account the presence of leptin receptor mRNA in ovarian tissue, demonstrated a direct effect of this hormone on rat granulosa cell steroidogenesis in vitro. At the same time, a dose-dependent inhibitory effect of leptin on IGF-1 was shown, potentiated by an increase in FSH-stimulated E 2 synthesis by granulosa cells. These data support the hypothesis that increased leptin levels in obese individuals may counteract dominant follicle maturation and ovulation. Very interesting are the data of Spicer and Franciso (1997), indicating that leptin in increasing concentrations (10-300 ng/ml) inhibits insulin-dependent production of E 2 and progesterone in granulosa cell culture. This effect is due to the presence of specific binding sites for leptin. By analogy with this, it can be assumed that a high level of leptin can reduce the sensitivity of other target tissues to the action of endogenous insulin, leading to the development of IR in obesity.

Diagnosis

Diagnosis of ovarian hyperandrogenism syndrome in typical clinical picture presents no difficulty. First of all, this is a violation of menstrual function by the type of oligo-, opso- or amenorrhea, anovulation and the primary or secondary infertility caused by it, hirsutism, acne, 40% of patients have obesity of varying severity. A gynecological examination reveals a bilateral increase in the size of the ovaries, often against the background of a hypoplastic uterus.

An important place in the diagnosis of PCOS is occupied by hormonal research methods. aimed at identifying hyperandrogenism, its source and determining the level of gonadotropic hormones: LH and FSH. In patients with PCOS, there is often a predominance of the level of LH over FSH, their ratio is disturbed and increased (more than 2.5-3). The level of prolactin is normal, although some increase is observed in 30% of patients.

The level of urinary excretion of total 17-CS in PCOS varies widely and is not very informative. Determination of 17-KS fractions (DGA, 11-oxidized ketosteroids, androsterone, etiocholanolone) also does not provide identification of the localization of the source of hyperandrogenism. Confirmation of the ovarian source of hyperandrogenism is an increase in the level of androstenedione (A) and testosterone (T) in the blood and an increase in the A / T ratio. The adrenal genesis of hyperandrogenism is confirmed by an increase in the level of dehydroepiandrosterone (DHA) and its sulfate (DHA-C) and 17-hydroxyprogesterone (17-OH-P) in the blood. To clarify the localization of the source of hyperandrogenism, various functional tests have been proposed, the most common of which is the test with dexamethasone, synacthen depot.

Taking into account the discovery of new pathogenetic links in the development of PCOS, to assess the state of carbohydrate metabolism, it is necessary to carry out a standard glucose tolerance test (75 ml of glucose per os) with the determination of glucose levels and immunoreactive insulin (IRI). Evidence in favor of insulin resistance is also a BMI over 25 and OT / OB over 0.85, as well as dyslipidemia.

Treatment

At the core modern approach to the pathogenetic treatment of PCOS lies the principle of restoring impaired ovarian function , that is, the elimination of anovulation, which in turn leads to a decrease in hyperandrogenism and the restoration of folliculogenesis. However, the study of the features of the etiopathogenesis of ovarian hyperandrogenism leads to the conclusion that the choice of methods for adequate treatment of PCOS is not an easy task.

Combined oral contraceptives - the most commonly used group of drugs for PCOS. The mechanism of action is to suppress elevated LH, normalize the LH / FSH ratio, increase the synthesis of SSSH by the liver. After cancellation, a “rebound effect” is achieved, which consists in the normalization of the hypothalamic-pituitary function, the reduction of androgen hyperproduction by ovarian tissue, the normalization of folliculogenesis and the restoration of ovulation.

Treatment is carried out according to the standard scheme: 1 tablet per day from the 5th to the 25th day of the cycle for 3-6 months. If necessary, the courses are repeated. However, it is known that long-term use estrogen-progestin contraceptives can lead to hyperinsulinemia, thereby aggravating the main pathogenetic link of PCOS.

Some contraceptives contain progestogen components derived from 19-norsteroids (norethisterone, levonorgestrel), which have varying degrees of androgenic effects, and therefore the prescription of drugs containing these components in patients with hirsutism is limited. It is more advisable for symptoms of hyperandrogenism to use oral contraceptives with a progestogen without androgenic action.

It is possible to use progestin preparations devoid of androgenic properties in the form of monotherapy, especially with endometrial hyperplasia. Dydrogesterone is prescribed 1 tablet (10 mg) 2 times a day from 14-16 to 25 days of the cycle lasting from 3 to 6 courses.

Most effective tool ovulation induction in PCOS is an antiestrogen drug clomiphene citrate . The main effects of antiestrogens are a decrease in pituitary hypersensitivity to the action of GnRH, a decrease in LH production, induction of an ovulatory LH surge, and stimulation of ovulation. The drug is prescribed at 50 mg, 100 mg per day from the 5th to the 9th day of the cycle until ovulation is reached according to the tests functional diagnostics, but no more than 3 courses in a row. Recently, there have been publications on the effect of clomiphene citrate on the insulin-insulin-like growth factor system. They indicated that by the 5th day of the stimulation of ovulation with clomiphene (150 mg/day), a progressive decrease (by a maximum of 30%) in the level of IGF-1 was determined. However, in a number of other similar studies, a significant decrease in basal insulin levels in response to the administration of clomiphene was not found.

The advent of drugs with antiandrogenic properties has greatly expanded the therapeutic options for PCOS. The most widely used drug is Diane-35, containing 35 mg of ethinyl estradiol and 2 mg of cyproterone acetate. In addition to the action characteristic of oral contraceptives, the drug blocks the action of androgens at the level of target cells, in particular, hair follicles. The latter leads to a decrease in hirsutism. The drug is used according to the standard scheme, as an oral contraceptive in courses of 6 or more cycles. However, it should be noted that these drugs have a negative effect on lipid and carbohydrate metabolism, which manifests itself in an increase in the level of cholesterol, low density lipoproteins, as well as an increase in hyperinsulinemia, which requires constant dynamic monitoring of these indicators in patients with PCOS. Spironolactone, which is widely used in the treatment of androgen-dependent dermopathies, also has antiandrogenic properties.

One of the main directions in the modern therapy of ovarian hyperandrogenism is the search and use of drugs and agents aimed at eliminating insulin resistance and compensatory hyperinsulinemia.

First of all, these are measures that ensure the reduction of excess body weight: a low-calorie diet (within 1500-2200 kcal / day) with restriction of fats and easily digestible carbohydrates, restriction of salt intake to 3-5 g per day, moderate exercise physical activity, normalization of the regime of work and rest. It is possible to use drugs that help reduce BMI, for example, orlistat, which selectively inhibits gastrointestinal lipases (“fat blocker”) or sibutramine, which blocks the reuptake of noradrenaline and serotonin in the synapses of the hypothalamic “satiation” center. Increased energy expenditure (thermogenesis) is also due to a synergistic interaction between enhanced function of norepinephrine and serotonin in the central nervous system. This is expressed in the selective activation of the central sympathetic effect on brown adipose tissue due to indirect activation of b 3 -adrenergic receptors.

The next step is the use of drugs that improve the impaired sensitivity of tissues to the action of insulin. There are data in the literature on the reduction of hyperandrogenism and the restoration of menstrual and ovulatory function when prescribing drugs of a number of biguanides (metformin /Siofor®/, Berlin-Chemie). They potentiate the action of insulin at the receptor and post-receptor levels and significantly improve the sensitivity of tissues to this hormone. Some studies have shown a significant decrease in fasting insulin levels and 2 hours after a 75 g glucose load in women with PCOS treated with metformin. This decrease correlated with a decrease in androgen levels. It should also be noted that the use of biguanides, which normalize carbohydrate disorders, often leads to a decrease in BMI in obese patients and has a positive effect on lipid metabolism.

The world literature reports the results of the use of drugs belonging to the class of thiazolidinediones. Studies have shown that during treatment troglitazone (200-400 mg / day) improves insulin sensitivity in women with PCOS, androgen levels decrease. However, the revealed cytotoxic, hepatotoxic effect of this group of drugs limits the possibility of their widespread use. A search is underway for new drugs that selectively affect insulin sensitivity.

Despite a significant arsenal of various agents used to treat ovarian hyperandrogenism, the therapy of this pathology should be comprehensive and consistent, taking into account the leading pathogenetic link at this stage of treatment.

Treatment of women with PCOS should be aimed not only at correcting the identified symptoms of this disease, but also at preventing possible future complications. It is very important to suppress the excess secretion of androgens and induce the stability of monthly menstrual bleeding, which is successfully achieved with the use of drugs with antiandrogenic properties (Diana-35).

In case of ineffectiveness of conservative therapy in a year, the question of surgical treatment can be raised - laparoscopy with wedge resection of the ovaries or their laser vaporization . The effectiveness of surgical treatment is high (up to 90-95% of ovulation recovery), and preliminary pathogenetic therapy increases the stability of the achieved result.

Ethinylestradiol + cyproterone acetate

Diane-35 (trade name)

(Shering AG)